Orexins are a family of homologous peptides including species orexin A, or OR-A, and orexin B, or OR-B. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell (1998), 92, 573-585). Orexins are produced in neurons of the lateral hypothalamus and bind to at least two distinct G-protein-coupled receptors, termed OX1 and OX2 receptors. The OX1 receptor is selective for OR-A, while the OX2 receptor can bind both OR-A and OR-B. Orexins are found to stimulate food consumption, regulate states of sleep and wakefulness, and may be involved in neural mechanisms of drug abuse and addiction.
There remains a need for small molecule modulators of orexin receptors, including OX1 and OX2, with desirable pharmaceutical properties. Certain difluoropyrrolidine compounds have been found in the context of this application to have this advantageous activity profile.